Beta Amyloid Hypothesis

Research over the last one and a half decades, focused on the pathobiology of AD support the hypothesis which includes the following:

A progressive cerebral accumulation of AB which initiates a complex multi-cellular cascade.

Neuritic dystrophy

Microgliosis

Astrocytosis

Neuronal dysfunction and loss

Synaptic alterations

Neurotransmitter deficits

This cerebral accumulation is due to a gradual and chronic imbalance in the production vs clearance of AB.

It is important to note that the accumulation of peptides in various formsrelate to both glial and neuronal dysfunction. However, only when such plaque-like lesions form are there enough cytotoxic AB species to initiate progressive cellular changes.

Updating the Amyloid Hypothesis

The hallmark of progressive deposition of insoluble fibrillar AB in senile plaques was proposed initially.

The magnitude of fibrillar AB load correlates poorly with severity of clinical dementia challenges the original hypothesis.

Many studies demonstrate that the best statistical correlation occurs with measures of synapse density and degree of dementia and not fibrillar AB load.

A new understanding suggests that soluble assembly states of AB peptides are better candidates for inducing neuronal and/or synaptic dysfunction.

These small soluble oligomers can cause cognitive decline by disrupting synaptic function in the absence of significant neuro-degeneration.